Prescription medication use in the 10 years prior to diagnosis of young onset Alzheimer’s disease: a nationwide nested case-control study

Background Patients with young onset Alzheimer’s disease (YOAD) face long diagnostic delays. Prescription medication use may provide insights into early signs and symptoms, which may help facilitate timely diagnosis. Methods In a register-based nested case-control study, we examined medication use for everyone diagnosed with YOAD in a Danish memory clinic during 2016–2020 compared to cognitively healthy controls. Prescription medication use were grouped into 13 overall categories (alimentary tract and metabolism, blood and blood forming organs, cardiovascular system, dermatologicals, genitourinary system and sex hormones, systemic hormonal preparations, antiinfectives for systemic use, antineoplastic and immunomodulating agents, musculo-skeletal system, nervous system, antiparasitic products, respiratory system, and sensory organs). Further stratifications were done for predetermined subcategories with a use-prevalence of at least 5% in the study population. Conditional logistic regression produced odds ratios, which given the use of incidence-density matching is interpretable as incidence rate ratios (IRRs). The association between prescription medication use and subsequent YOAD diagnosis was examined in the entire 10-year study period and in three time-intervals. Results The study included 1745 YOAD cases and 5235 controls. In the main analysis, several overall categories showed significant associations with YOAD in one or more time-intervals, namely blood and blood forming organs and nervous system. Prescription medication use in the nervous system category was increased for YOAD cases compared to controls already 10->5 years prior to diagnosis (IRR 1.17, 95% CI 1.05–1.31), increasing to 1.57 (95% CI 1.39–1.78) in the year preceding diagnosis. This was largely driven by antidepressant and antipsychotic use, and especially prominent for first-time users. Conclusions In this study, medication use in several categories was associated with YOAD. Onset of treatment-requiring psychiatric symptoms such as depression or psychosis in mid-life may serve as potential early indicators of YOAD. Supplementary Information The online version contains supplementary material available at 10.1186/s13195-024-01523-7.


Entry in DanDem
The ATC main group "Various" were omitted from all analyses due to low number of observations.Figure S1 legend: Incidence rate ratios (IRRs) for young onset Alzheimer's disease are plotted by first-ever prescriptions, compared to no prescriptions, in the nervous system subcategories in the 10-year retrospective study period and in three time-intervals prior to diagnosis.Conditional logistic regression analyses produced odds ratios, which given the use of incidence-density matching is interpretable as IRRs.For the refence group (dementia-free controls), the IRR is equal to 1 (as indicated by the dotted vertical line).Error bars represent 95% confidence intervals (CI).S2).

Figure S2 .
Figure S2.Sensitivity analysis: Incidence rate ratios by overall medication category in the 10-year study period, for the entire study population and divided by disease severity at time of diagnosis.

Figure S2 legend:
Figure S2 legend:Incidence rate ratios (IRRs) for young onset Alzheimer's disease are plotted by overall medication categories in the 10-year retrospective study period and in three time-intervals prior to diagnosis for the entire study population and divided by disease severity at time of diagnosis.Conditional logistic regression analyses produced odds ratios, which given the use of incidence-density matching is interpretable as IRRs.For the refence group (dementia-free controls), the IRR is equal to 1 (as indicated by the dotted vertical line).Error bars represent 95% confidence intervals (CI).The IRRs presented are adjusted for age, sex, highest attained educational level at age 40 years (or at time of diagnosis if age at diagnosis <40 years), and civil status at index date.Unadjusted estimates are presented in tableS7.* Not including dementia medication (see ATC-codes used in tableS2).

Figure S3 .
Figure S3.Sensitivity analysis: Incidence rate ratios by overall medication category in the 10-year study period and in time intervalsfor the entire study population and stratified by age.

Figure S3 legend:
FigureS3legend: Incidence rate ratios (IRRs) for young onset Alzheimer's disease are plotted overall medication categories in the 10-year retrospective study period and in three time-intervals prior to diagnosis for the entire study population and stratified by age.Conditional logistic regression analyses produced odds ratios, which given the use of incidence-density matching is interpretable as IRRs.For the refence group (dementia-free controls), the IRR is equal to 1 (as indicated by the dotted vertical line).Error bars represent 95% confidence intervals (CI).The IRRs presented are adjusted for age, sex, highest attained educational level at age 40 years (or at time of diagnosis if age at diagnosis <40 years), and civil status at index date.Unadjusted estimates are presented in tableS8.* Not including dementia medication (see ATC-codes used in tableS2).

Figure S4 .
Figure S4.Sensitivity analysis: Incidence rate ratios by overall medication category in the 10-year study period and in time intervalsfor the entire study population and divided by sex.

Figure S4 legend:
Figure S4 legend:Incidence rate ratios (IRRs) for young onset Alzheimer's disease are plotted by overall medication categories in the 10-year retrospective study period and in three time-intervals prior to diagnosis for the entire study population and divided by sex.Conditional logistic regression analyses produced odds ratios, which given the use of incidence-density matching is interpretable as IRRs.For the refence group (dementia-free controls), the IRR is equal to 1 (as indicated by the dotted vertical line).Error bars represent 95% confidence intervals (CI).The IRRs presented are adjusted for age, highest attained educational level at age 40 years (or at time of diagnosis if age at diagnosis <40 years), and civil status at index date.Unadjusted estimates are presented in tableS9.* Not including dementia medication (see ATC-codes used in tableS2).

Table S2 .
X Overall categories, subcategories, and corresponding ATC codes

Table S3 .
Incidence rate ratios for medication use in overall categories, overall and in time-intervals

hormonal preparations, excluding sex hor- mones and insulin H
*Dementia medication (tableS1) is omitted in the conditional logistic regression

Table S4 .
Incidence rate ratios for medication use in subcategories (nervous system products presented in tableS5)

Table S5 .
Incidence rate ratios for medication use in nervous system subcategory in time-intervals

Table S6 .
Post-hoc analysis -Incidence rate ratios for first-ever medication use in nervous system subcategory (compared to never-users) Incidence rate ratios for medication use in nervous system subcategory in time intervals (first prescriptions only) The IRRs presented are adjusted for age, sex, highest attained educational level at age 40 years (or at time of diagnosis if age at diagnosis <40 years), and civil status at index date.Unadjusted estimates are presented in table S6.
The IRRs presented are adjusted for age, sex, highest attained educational level at age 40 years (or at time of diagnosis if age at diagnosis <40 years), and civil status at index date.Unadjusted estimates are presented in table S7. * Not including dementia medication (see ATC-codes used in tableS2).
The IRRs presented are adjusted for age, sex, highest attained educational level at age 40 years (or at time of diagnosis if age at diagnosis <40 years), and civil status at index date.Unadjusted estimates are presented in table S8. * Not including dementia medication (see ATC-codes used in tableS2).
The IRRs presented are adjusted for age, highest attained educational level at age 40 years (or at time of diagnosis if age at diagnosis <40 years), and civil status at index date.Unadjusted estimates are presented in table S9. * Not including dementia medication (see ATC-codes used in table